B3.051 Prework Aplastic Anemia Flashcards
how is severe aplastic anemia classified?
bone marrow cellularity <30% depression of at least 2 of the following 3 hematopoietic lineages: -neutrophil < 0.5 -retic <60 w transfusion dependence -platelet <20
how is moderate aplastic anemia classified
decreased bone marrow cellularity
depression of 2/3 lineages not fulfilling the prior criteria
what is fanconi anemia
most common cause of inherited bone marrow failure syndrome (IBMFS)
autosomal recessive
chromosomes particularly susceptible to DNA cross linking agents
what genetic defect leads to fanconi?
at least 16 defined
most common is a mutation in FANCA on chrom 16
most mutations mess up cellular response to DNA damage, especially interstrand cross linking
what agents are used to test for fanconi?
ICL agents
DEB or MMC
what is dyskeratosis congenita
another cause of IBMFS
mutations in genes of the telomere repair complex leading to premature death of rapidly proliferating cells
X-linked more common
genetic defects associated with DC
X linked: DKC1 gene
autosomal dom: TERC and TERT
2 other causes of IBMFS
shwachman-diamond syndrome
severe congenital neutropenia
pathogenesis of shwachman-diamond syndrome
exocrine pancreatic insufficiency with secondary steatorrhea, blood cell deficiencies, and skeletal abnormalities
mutations in the SBDS genes on 7q11 which induced accelerated cellular apoptosis via the FAS pathways
pathogenesis of severe congenital neutropenia
heterozygous mutations in the ELA2/ELANE gene
why rule out inherited causes?
treatment different, immune suppression doesn’t work
at risk of other medical problems including cancer
family needs genetic counseling
causes of primary acquired aplastic anemia
idiopathic aplastic anemia
pregnancy-associated aplastic anemia
AA/PNH syndrome
causes of secondary acquired
drug associated iatrogenic/cytotoxic idiosyncratic radiation associated viruses (EBV, CMV) hepatitis/ aplastic anemia syndrome pancytopenia of autoimmune disease
what is PNH
paroxysmal nocturnal hemoglobinuria
rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias
the absence of 2 GPI anchored proteins, CD 55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations
due to somatic mutations
what are 2 ways that pathogens can affect hematopoietic stem cells
direct toxic effects
indirect effects through immunologic mediation
supportive measures for aplastic anemia
symptoms can be corrected with transfusions
infections addressed with broad spectrum antibiotics in presence of fever and severe neutropenia
overuse of blood products should be avoided, as they may cause allo-immunizations
what is the preferred first therapy in young people with AA
matched sibling HSCT
bone marrow is preferred source of stem cells, not peripheral blood
discuss the primary immunosuppressive therapy agent used for AA
principal agent is ATG (anti-thymocyte globulin) which is manufactured by delivering human T cells to a horse/rabbit
immunized animals produce Abs to the Ags on the T cell
removed and purified and administered to human to deplete lymphocytes
what is ATG used in combo with
cyclosporine
calcineurin inhibitor that inhibits IL-2 production
prednisone used as prophylaxis for serum sickness
discuss eltrombopag
TPO receptor agonist
improves blood counts
response rate of 40%
time to response to h-ATG/CsA therapy
10-12 weeks
response rate 60-80%
cause of AGVHD
mature donor T cells present in the allograft acting against host “antigens”
initiating trigger is believed to be epithelial cell injury
most prone tissues are skin, GI mucosa, and bile ducts
cause of CGVHD
beyond 100 days
mainly mediated by new T and B cells that are derived from HSCs or other early progenitors in the graft
more indolent course
presentation of AGVHD
rash, diarrhea, elevated liver function tests
severe cases can lead to sepsis
what tumor is most affected by graft versus tumor effect?
CML
